Epidermal Nonpeptidergic Nerves Modulate Cutaneous Immunity

摘要 皮肤是一个高度神经支配的器官，含有大量的感觉传入神经元， 对各种刺激作出反应，包括触摸、致痒剂（引起瘙痒）和有害物质。 药物（引起疼痛）。也有许多皮肤驻留免疫细胞包括树突细胞 以及与感觉神经元直接接触的肥大细胞。最近， 我很欣赏皮肤感觉神经元和皮肤固有免疫细胞的工作原理， 协同地引发局部炎症和宿主防御。我们之前已经证明， 感觉疼痛的TRPV 1+神经元对于皮肤先天性17型是必要和足够的。 炎症和宿主对C.白色念珠菌因此，与以下各项关联的神经元子集 疼痛刺激是必要的，足以驱动17型免疫反应，这是 针对可引起疼痛刺激的细胞外病原体的最佳免疫应答。我们 现在提出测试非肽能感觉神经元的免疫潜力， 基于单细胞RNAseq可分为至少3个子集：NP 1、NP 2和NP 3。的 该提案的总体目标是了解各个子集的独特贡献， 非肽能感觉神经元对皮肤免疫的调节。探索这个神经- 免疫相互作用将更好地定义驱动炎症的细胞回路， 靶向神经元亚群的激动剂/拮抗剂的用途 皮肤免疫反应而没有全面的免疫抑制。具体来说，我们假设 NP 1感觉神经的功能是抑制肥大细胞的活性。我们进一步假设， 响应于致痒原而传递痒感的NP 2和NP 3亚群也 参与类似于TRPV 1+神经元的2型免疫应答的发展， 17型免疫反应调节Th 2和肥大细胞功能的潜力使得这些细胞能够在体内发挥作用。 过敏性疾病发病机制的潜在关键途径。

Abstract The skin is a highly innervated organ and contains numerous sensory afferent neurons that respond to a diverse array of stimuli including touch, pruritogens (inducing itch) and noxious agents (inducing pain). There are also many skin-resident immune cells including dendritic cells and mast cells that make direct contact with sensory neurons. It has very recently become appreciated that cutaneous sensory neurons and skin-resident innate immune cells work synergistically to initiate local inflammation and host defense. We have previously shown that TRPV1+ neurons that sense pain are necessary and sufficient for cutaneous innate Type-17 inflammation and host defense against C. albicans. Thus, a neuron subset associated with painful stimuli is necessary and sufficient to drive a Type-17 immune response which is the optimal immune response against extracellular pathogens that can cause painful stimuli. We now propose to test the immunologic potential of nonpeptidergic sensory neurons are that can be divided based on single cell RNAseq into at least 3 subsets: NP1, NP2, and NP3. The overall goal of this proposal is to understand the unique contribution of individual subsets of nonpeptidergic sensory neurons to the modulation of skin immunity. Exploring this neuro- immune interaction will better define the cellular circuits driving inflammation and allow for the use of agonists/antagonists that target neuron subsets in order to modulate specific types of cutaneous immune responses without global immunosuppression. Specifically, we hypothesize that NP1 sensory nerves function to suppress mast cell activity. We further hypothesize that the NP2 and NP3 subsets that communicate itch sensation in response to pruritogens also participate in the development of Type-2 immune responses analogous to TRPV1+ neurons and Type-17 immune responses. The potential to modulate Th2 and mast cell function makes these pathways potential key for allergic disease pathogenesis.